Alzheimer's disease, a progressive, neurodegenerative disease of the central nervous system, is the most common form of dementia. It is estimated that 44 million people worldwide have Alzheimer’s disease or a related dementia. Alzheimer’s disease has proved difficult to treat, mainly because the symptoms of the disease only emerge years after disease onset. The treatments that are currently available for Alzheimer’s disease only help to ease the symptoms of the disease; they do not slow or stop its progression. The goal of Alzheimer’s disease research is to develop effective therapies that stop or prevent the underlying cause of the disease.
In a recent edition of Science, Professor Michal Schwartz of the Weizmann Institute of Science, provided insight into the potential use of immunotherapy to treat Alzheimer’s disease. Researchers in this field hypothesize that like cancer, in which cancer cells hijack the immune system to avoid being attacked, the progression of Alzheimer’s disease pathology may be due to suppression of the peripheral immune system, impairing the body’s ability to mount an effective immune response. Immunotherapy treatment for cancer, which aims to use a patient’s own immune system to target and kill cancer cells, has been showing great promise. In this Science Perspectives article, Professor Schwartz reviews recent research (some of which are summarized below) that suggest a comparable approach to treat Alzheimer’s disease might exhibit similar success.
In a Nature Medicine article, Town et al. genetically induced the expression of a CD11c promoter-driven, dominant-negative form of TGF-beta RII (CD11c-DNR) in the Tg2576 mouse model of Alzheimer’s disease. The authors showed that this dominant negative receptor blocked TGF-beta / Smad2/3 signaling in peripheral macrophages, but not microglia, in the transgenic mice. Additionally, they reported that the Tg2576 mice expressing CD11c-DNR exhibited less astrogliosis and partial improvement of cognitive function compared to their control littermates. The authors attributed these effects in the transgenic mice to an increase in the number of peripheral macrophages located around cerebral vessels and Amyloid beta plaques, and to an increase in the phagocytosis of Amyloid beta by these macrophages.
Baruch et al. reported in Nature Communications that the 5XFAD transgenic mouse model of Alzheimer’s disease exhibited elevated levels of splenocyte FoxP3+ regulatory T cells (Tregs), decreased levels of IFN-gamma in the choroid plexus, the epithelial barrier between the blood and cerebrospinal fluid, and reduced choroid plexus expression of the leukocyte homing and trafficking molecules ICAM-1/CD54, VCAM-1/CD106, CXCL10/IP-10/CRG-2, and CCL2/JE/MCP-1. They hypothesized that systemic immunosuppression mediated by Tregs reduces the number of IFN-gamma producing cells in the choroid plexus, resulting in choroid plexus gateway dysfunction and fewer immune cells transmigrating into the brain. They showed that temporary depletion of splenocyte Tregs, or pharmacological inhibition of their activity, increased IFN-gamma levels and the expression of leukocyte trafficking molecules in the choroid plexus, augmented the number of immunoregulatory cells (e.g. monocyte-derived macrophages and Tregs) detected at Amyloid beta plaques, and alleviated Alzheimer’s disease pathology, as measured by increased Amyloid beta plaque clearance, reduced neuroinflammation, and improved cognitive function.
The main role of the immune checkpoint molecules PD-1/PD-L1 is to negatively regulate T cell and B cell activity. New cancer treatments are beginning to use antibody-mediated blockade of these molecules since cancer cells can express PD-L1/B7-H1, which then interacts with PD-1 on activated T cells to negatively regulate the responses of these immune cells. Baruch et al. reported in Nature Medicine that blocking PD-1, via intraperitoneal administration of an anti-PD-1 blocking antibody, in the 5XFAD transgenic mouse model of Alzheimer’s disease resulted in increased levels of IFN-gamma in the choroid plexus and elevated numbers of monocyte-derived macrophages in the brain. They also reported that PD-1 blockade reduced cerebral Amyloid beta plaque load, astrogliosis, and cognitive deficits in these mice.
This web page provides links to resources from R&D Systems for studying different immunotherapy strategies.
This brochure outlines the different co-signaling molecules that regulate T cell activation, and lists the products from R&D Systems that can be used to study the effects of T cell co-signaling molecules.
This web page provides links to resources from R&D Systems for researching immune checkpoint molecules, including checkpoint-blocking antibodies.
This interactive pathway outlines the specific Treg-associated molecules that are involved in the different mechanisms utilized by Tregs to suppress immune responses.
This interactive pathway outlines the molecular mechanisms involved in APP processing, Amyloid beta secretion, and plaque formation.
These immunoassays are designed to measure Amyloid beta (1-40) and (1-42) in cell culture supernates, tissue lysates, and cerebrospinal fluid. Unlike competitors’ kits, these ELISAs use recombinant antibodies and non-aggregating mimetic standards to avoid lot-to-lot inconsistencies and misleading results.
This wall poster illustrates the mechanisms by which Amyloid beta plaques initiate neuroinflammation and neuronal death.
This interactive pathway outlines the signaling pathways activated by different leukocyte trafficking molecules and the changes that are induced to increase the permeability of the blood-brain barrier and promote transmigration of peripheral immune cells.